Sandhoff disease is an autosomal recessive lysosomal storage disorder caused by deficiency of two components of the hexosaminidase enzyme, called beta-hexosaminidase-A (HEX A) and beta-hexosaminidase B (HEX B). When functioning normally, this complex is responsible for breaking down a fatty substance in the lysosomes called GM2 ganglioside. Deficiency of this complex causes accumulation the GM2 ganglioside substance in the lysosomes, particularly in the brain. Symptoms become evident in the first 6 months of life and include progressive neurodegeneration, early blindness, mental and motor deterioration, doll-like face, cherry red spots on the retina and macrocephaly. Death typically occurs between 2-4 years of age. A variant form of Sandhoff disease, characterized by a later age of onset and milder clinical progression, is associated with residual enzymatic activity and can be caused by a variety of mutations.
There are three protein components to the hexosaminidase complexes: the alpha subunit, the beta subunit and the GM2 ganglioside activator protein. Deficiency of the alpha subunit, due to mutations in the HEXA gene, results in deficiency of the hexosaminidase A complex and causes Tay-Sachs disease. Deficiency of the beta subunit, due to mutations in the HEXB gene, results in deficiency of both the beta-hexosaminidase A and B complexes and causes Sandhoff disease. Deficiency of the GM2 ganglioside activator protein, due to mutation in the GM2A gene, is associated with the rare AB variant form of GM2 gangliosidosis. Enzymatic analysis can distinguish between the GM2 gangliosidoses. Clinically, these diseases are indistinguishable.
Mutations in the HEXB gene cause Sandhoff disease. There have been more than 25 different mutations identified in the HEXB gene. Diagnostic sequencing analysis of the HEXB gene coding region is available for patients with Sandhoff disease and their at-risk relatives on a clinical basis.
For questions about testing for Sandhoff disease, call EGL Genetics at 470-378-2200 or 855-831-7447.
For further clinical information about lysosomal storage diseases, including management and treatment, call the Emory Lysosomal Storage Disease Center at (404) 778-8565 or (800) 200-1524.
1). O'Dowd, B. et al. Molecular heterogeneity in the infantile and juvenile forms of Sandhoff disease (O-variant GM2 gangliosidosis). J. Biol. Chem. 261: 12680-12685, 1986.
This test is indicated for:
- Confirmation of a clinical diagnosis of Sandhoff disease in individuals who have tested negative for sequence analysis
- Carrier testing in adults with a family history of Sandhoff disease who have tested negative for sequence analysis
Results of molecular analysis must be interpreted in the context of the patient's clinical and/or biochemical phenotype.
Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
- Sequence analysis of the HEXB gene is available and is required before deletion/duplication analysis.
- Prenatal testing is available to couples who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.